Arsenic (As) is one of the most common naturally occurring environmental contaminants. Its highest accumulation is in water where the predominant As species are the toxic inorganic forms (arsenate and arsenite). Until 2006, the regulated dose for As was 50 parts per billion (ppb) but in response to the research on As and cancer, the EPA lowered the regulation to 10ppb. At high exposures, As has been associated with skin, lung and bladder cancers, vascular diseases, hypertension, genotoxicity, and diabetes. While the carcinogenic potential of heavy As exposure has received much attention, studies suggest that moderate As exposure also poses a threat to human cognitive development. Learning deficits related to As toxicity have been characterized through epidemiological studies, many of which come from adolescents in other countries with significantly higher As concentrations (>50 ppb). Preliminary research in our laboratory at the SOppb As concentration has revealed deficits in learning behavior tasks in our perinatal As-exposed mouse model. The aim of this project is to determine if environmentally relevant concentrations of As (SOppb) produce learning deficits in mice and to use this model to elucidate the mechanism of moderate As toxicity on the brain. We will use two different paradigms;the first is a perinatal As exposure and the second, an acute post-weaning exposure. Specific aims of the project include: 1) To test the effect of SOppb As in drinking water on learning behavioral parameters in adolescent mouse offspring, 2) to assess the impact of As-exposure on stress axis parameters, including glucocorticoid receptor (GR), 3) to determine the impact of As on the MAPK signaling cascades important for learning, and 4) to evaluate the level of GR binding to the glucocorticoid response element (GRE) site on Ras and Raf promoters. Detection of learning behavioral deficits will include novel object recognition task and 8-way radial arm maze. Radioimmunoassay will be used to determine hormone levels of the offspring and differential centrifugation and western blot will be used to measure receptors. MAPK signaling cascades will be measured using RT-PCR and western blot. Chromatin Immunoprecipitation Real-Time PCR will be used to assess the GR interaction with the GRE and confirm the altered binding profiles of active and repressive histone marks on these genes. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will reveal whether or not arsenic exposure, at levels reflecting drinking water concentrations in the US, is detrimental to learning. It will also give some indication of time periods (developmental vs. exposure after birth) when adolescents would be particularly susceptible to damage by arsenic in their drinking water and it will provide a mechanism for arsenic damage in the brain.